Lead Modification

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Lead Modification

• Objectives Once a lead compound has been
  identified it must be systematically altered to
  obtain the desired properties (maximize the
  therapeutic index and minimize side effects).  
  Alternatively, a known agonist or substrate can
  be structurally modified to make an antagonist or
  an inhibitor by maintaining the structural
  characteristics associated with binding and
  specificity but not "activation" of the
  biological activity (e.g. the HIV protease
  inhibitors where the lead compound was the
  substrate). At the end of this lecture the
  student will know the concepts of therapeutic
  index and of the pharmacophore, based on the
  opioids, and the traditional methods used for
  optimization of lead compounds to improve their
  biological activity.

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Oral contraceptives are an example
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Therapeutic index (therapeutic ratio)

• measure of the ratio of undesirable to desirable
  drug effects (multiple bioassays)
• in vivo LD50/EC50 therapeutic index    LD50
  the lethal dose for 50 of the test animals   
  EC50 the effective dose that produces the
  maximum therapeutic effect in 50 of the test
  animals
• The larger the therapeutic index the greater the
  safety of the drug goal of lead optimization

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Pharmacophore

• Pharmacophore identification via functional group
  modification
• 1) systematically alter or remove portions of the
  molecule
• 2) identify regions essential for activity (or
  different types of activities)
• 3) note that pharmacological data is sometimes
  ambiguous (i.e. data is not clear cut yes or no,
  but often somewhere in between), requiring care
  when interpreting relationships of structure to
  activity.

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Opioids as an example of a functional group
modification to identify a pharmacophore
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Remove tetrahydrofuran ring and hydroxyl at R'
i) levorphanol ii) 3-4 times more potent as an
analgesic than morphine iii) maintains addictive
properties iv) therefore, tetrahydofuran ring
and R' hydroxyl not essential for activity
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Removal of half of the cylcohexene ring
i) benzomorphan partial separation of analgesic
and addictive properties ii) cyclazocine and
pentazocine much lower addictive properties
iii) therefore, cyclohexene ring contributes to
the addictive properties
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Removal of all fused rings
i) Demerol 10-12 potency of morphine ii)
therefore, final fused ring not essential for
analgesic activity
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Acyclic analog
i) Darvon 1/2 to 2/3 as potent as codeine ii)
Methadone as potent an analgesic as morphine
less, but, still addictive iii) therefore,
conformation of the substituents, not the rings
themselves are important for activity
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Structure of opioid pharmacophore
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Increase rigidity and/or structural complexity
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Functional group modification
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Homologation
Relationship of potency to the number of
methylene group
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Chain branching
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Primary through quarternary amines
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Chain branching (continued)
10-aminoalkylphenothiazine 1) -CH2CH(CH3)N(CH3)2
(promethazine) 2) -CH2CH2N(CH3)2 (diethazine)
     for 1 and 2 antispasmodic and
antihistaminic 3) -CH2CH2CH2N(CH3)2 (promazine)
     decreased antispasmodic and antihistaminic
activities      has sedative and tranquilizing
activities 4) -CH2CH(CH3)CH2N(CH3)2
(trimeprazine)      reduced tranquilizing
activity      antipruritic (anti-itch) activity
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Ring-Chain Transformations
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Isosteres

• Functional groups with similar properties
  (structural or chemical, such as hydrogen bonding
  ability).
• Often used to modify lead compound activity (i.e.
  fine tune biological activity) in order to     
  minimize toxicity      alter metabolism     
  maximize bioavailability

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Classical isosteres

• i) groups that have the same number of valence
  electrons but may have different numbers of atoms
• ii) atoms, ions or molecules in which the
  peripheral layers of electrons can be considered
  identical

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Examples of classical isosteres

• Univalent atoms and groups (note the same number
  of total or valence electrons)   Series A) CH3
  NH2 OH F Cl    Series B) Cl PH2 SH    Series
  C) Br i-Propyl    Series D) I t-Butyl
• Bivalent atoms and groups   Series A) -CH2-
  -NH- -O- -S- -Se-    Series B) -COCH2R -CONHR
  -CO2R -COSR
• Trivalent atoms and groups   Series A) -CH -N
     Series B) -P -As
• Tetravalent atoms   Series A) C Si    Series
  B) C N() P()
• Ring equivalents (e.g. these functional groups
  are in the rings)   Series A) -CHCH- -S- (eg.
  benzene versus thiophene)    Series B) -CH -N
  (eg. benzene versus pyridine)    Series C) -O-
  -S- -CH2- -NH- (eg. tetrahydrofuran vs.
  tetrahydrothiophene vs. cyclopentane vs.
  pyrrolidine)

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(Nonclassical) Bioisosteres

• Not included with classical isosteres
• Will contain at least one similar physical
  property, although structures can differ
  significantly
• Properties considered in bioisosteressize shape
  hydrophobicitypKa chemical reactivity
  hydrogen bonding capacity

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Examples of bioisosteres for the carbonyl and
carboxylate groups
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Examples of bioisosteres for hydrogen, hydroxyl
groups, halogens, and a methylene spacer
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Use of bioisosteres allows for testing the
biological role of functional groups

• Structural
• Receptor interactions
• Pharmacokinetics
• Metabolism

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Comparison of 10-aminoalkylphenothiazine and the
-CH2CH2- analog